Genetic Variant IRF3:c.-48T>C (chr19-49665670-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001571.6(IRF3):c.-48T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IRF3
NM_001571.6 5_prime_UTR

Scores

Splicing: ADA: 0.0001454

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.644

Publications

28 publications found

Variant links:

Genes affected

IRF3 (HGNC:6118): (interferon regulatory factor 3) This gene encodes a member of the interferon regulatory transcription factor (IRF) family. The encoded protein is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP. This complex translocates to the nucleus and activates the transcription of interferons alpha and beta, as well as other interferon-induced genes. The protein plays an important role in the innate immune response against DNA and RNA viruses. Mutations in this gene are associated with Encephalopathy, acute, infection-induced, herpes-specific, 7. [provided by RefSeq, Sep 2020]

IRF3 links:

BCL2L12 (HGNC:13787): (BCL2 like 12) This gene encodes a member of a family of proteins containing a Bcl-2 homology domain 2 (BH2). The encoded protein is an anti-apoptotic factor that acts as an inhibitor of caspases 3 and 7 in the cytoplasm. In the nucleus, it binds to the p53 tumor suppressor protein, preventing its association with target genes. Overexpression of this gene has been detected in a number of different cancers. There is a pseudogene for this gene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

BCL2L12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001571.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IRF3	NM_001571.6	MANE Select	c.-48T>C	5_prime_UTR	Exon 1 of 8	NP_001562.1	Q14653-1
IRF3	NM_001197122.2		c.-48T>C	5_prime_UTR	Exon 1 of 8	NP_001184051.1	Q14653-4
IRF3	NM_001197123.2		c.-211T>C	5_prime_UTR	Exon 1 of 8	NP_001184052.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IRF3	ENST00000377139.8	TSL:1 MANE Select	c.-48T>C	5_prime_UTR	Exon 1 of 8	ENSP00000366344.3	Q14653-1
IRF3	ENST00000601291.5	TSL:1	c.-48T>C	5_prime_UTR	Exon 1 of 8	ENSP00000471896.1	Q14653-4
IRF3	ENST00000599223.5	TSL:1	c.-48T>C	5_prime_UTR	Exon 1 of 7	ENSP00000471358.1	Q14653-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000340

AC:

AN:

882752

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

442500

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

20620

American (AMR)

AF:

0.00

AC:

AN:

22486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16426

East Asian (EAS)

AF:

0.00

AC:

AN:

35440

South Asian (SAS)

AF:

0.00

AC:

AN:

55950

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2708

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

656576

Other (OTH)

AF:

0.00

AC:

AN:

40070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

2838

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

6.7

(source)

DANN

Benign

0.66

PhyloP100

-0.64

PromoterAI

-0.0094

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over